Structural Investigations of 13-O-Demethyl-FK506 and Its Isomers Generated by in vitro Metabolism of FK506 Using Human-Liver Microsomes

✍ Scribed by Wolfgang Schüler; P. Schmieder; Horst Kessler; Uwe Christians; Ines Holze; Karl-Friedrich Sewing; Hans-Martin Schiebel

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: German
• Weight: 775 KB
• Volume: 76
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.19930760614

✦ Synopsis

FK506 is currently under investigation as immunosuppressant after organ transplantation and in immune diseases. The structure of a demethylated metabolite 1 of FK506 isolated after in oitro metabolism by human-liver microsomes was established using two-dimensional homo-and heteronuclear NMR experiments. The demethylation position was found to be at 0-C( 13) using HMBC spectra. In contrast to FK506, 7 different isomers could be differentiated in COSY, HMBC, and HMQC spectra. The intensity of their signals was 50: 18: 11 :9:6:6 (one isomer could not be quantified). This isomerization may be explained by epimerization at C(10) or alternative formations of the hemiketal ring between C(10) and C(13) or C(9) and C( 13), in addition to cisltrans-isomerism about the amide bond (see Scheme). The structural variation is possible by participation of the OH group at C(13) formed after demethylation and could be derived from HMBC spectra. Chemical exchange evidenced by ROESY spectra proved the rotational isomerism. NMR investigation of the structure of 13-0 -demethyl-FK506 (1) revealed at least seven isomers.